The LIM domain only 4 (LMO4) protein is expressed in the hypothalamus, but its function there is not known. Using mice with LMO4 ablated in postnatal glutamatergic neurons, including most neurons of the
paraventricular (PVN) and ventromedial (VMH) hypothalamic nuclei where LMO4 is expressed, we asked whether LMO4 is required for metabolic homeostasis. LMO4 mutant mice exhibited early onset adiposity. These mice
had reduced energy expenditure and impaired thermogenesis together with reduced sympathetic outflow to adipose tissues. The peptide hormone leptin, produced from adipocytes,activates Jak/Stat3 signaling at the hypothalamus to control food intake, energy expenditure, and fat metabolism.
Intracerebroventricular infusion of leptin suppressed feeding similarly in LMO4 mutant and control mice.However, leptin-induced fat loss was impaired and activation of Stat3 in the VMH was blunted in these mice. Thus, our study identifies LMO4 as a novel modulator of
leptin function in selective hypothalamic nuclei to regulate fat metabolism.